1 / 47

David Miles Chair at the Mount Vernon Cancer Centre, Middlesex, UK

David Miles Chair at the Mount Vernon Cancer Centre, Middlesex, UK. Past Senior Lecturer and Consultant in Medical Oncology at Guy’s and St Thomas’ Hospital, London

chacha
Download Presentation

David Miles Chair at the Mount Vernon Cancer Centre, Middlesex, UK

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. David MilesChair at the Mount Vernon Cancer Centre, Middlesex, UK • Past Senior Lecturer and Consultant in Medical Oncology at Guy’s and St Thomas’ Hospital, London • Received awards from the British Association of Cancer Research, the American Society of Clinical Oncology and the American Association for Cancer Research • Published numerous papers on breast cancer and biological therapies • On Institutional Review Board for Cancer Research UK and UK National Institute for Clinical Excellence committee for the treatment of early stage breast cancer Mount Vernon Hospital

  2. Innovation + strength = effective management for HER2-negative metastatic breast cancer David Miles Mount Vernon HospitalMiddlesex, UK

  3. Introduction • Breast cancer is the leading cause of cancer mortality in women worldwide • Improvements in detection and therapy of early breast cancer have greatly improved survival • many patients still go on to develop recurrent or metastatic disease • Aims of therapy for systemic disease • slow/halt disease progression • extend survival • maintain patient QoL through symptom relief QoL = quality of life

  4. Metastatic breast cancer (MBC) Aggressive visceral disease Other metastatic patterns Potentially hormone responsive Premenopausal Postmenopausal No responseor onprogression Ov Abl  Tamoxifen Tamoxifen No response Ov Abl  AI AI on progression CYTOTOXIC CHEMOTHERAPY WITH OR WITHOUT TRASTUZUMAB Ov Abl = ovarian ablation; AI = aromatase inhibitor

  5. AIs (letrozole) SERDS (faslodex) SERMS (tamoxifen) Anthracyclines Taxanes Capecitabine Vinorelbine Various Changing options in MBC (1980s) First line Second line Third line SERMS = selective oestrogen-receptor modulators SERDS = selective oestrogen-receptor down regulators

  6. AIs (letrozole) SERDS (faslodex) SERMS (tamoxifen) First line Anthracyclines Taxanes Capecitabine Vinorelbine Various Changing options in MBC (1990s) Second line ± trastuzumab

  7. AIs (letrozole) SERDS (faslodex) SERMS (tamoxifen) First line Anthracyclines Taxanes Capecitabine Vinorelbine Various Changing options in MBC (2000s) ± trastuzumab

  8. Treatment scenario 1 • You are treating a patient with the following characteristics • 62-year-old woman • HER2-negative, hormone receptor-negative MBC • metastasis to bone • no prior chemotherapy for metastatic disease • adjuvant therapy with both doxorubicin and paclitaxel2 and a half years previously • did not tolerate taxane well (neuropathy) • What treatment would you recommend?

  9. Enzymatic activation of capecitabine Capecitabine Capecitabine Tumour CE 5'-DFCR 5'-DFCR Intestine CyD CyD 5'-DFUR 5'-DFUR Thymidine phosphorylase (TP) Liver 5-FU 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxyl esterase; 5-FU = 5-fluorouracil

  10. 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU 5-FU More 5-FU in the tumour with TP-activated capecitabine x 3.2* x 21.4* Tumour tissue Normal tissue Plasma *Ratio of median values Schüller J, et al. Cancer Chemother Pharmacol 2000;45:291–7

  11. Capecitabine monotherapy has activity in first-line MBC (phase II trials) *Includes patients receiving a taxane following capecitabine monotherapy; †PFS C = capecitabine; RR = response rate;TTP = time to progression; OS = overall survival;PFS = progression-free survival 1O’Shaughnessy J, et al. Ann Oncol 2001;12:1247–54 2Soto C, et al. J Clin Oncol 2006;24(Suppl. 18):20s (Abstract 570)3Bajetta E, et al. J Clin Oncol 2005;23:2155–61

  12. Key phase III trial of first-linecapecitabine monotherapy versus oral CMF RANDO MIS ATION • Primary endpoints: PFS (efficacy), quality-adjusted PFS (effectiveness) • Secondary endpoints: RR, health-related QoL, OS and safety Intermittent capecitabine 1,000mg/m2 b.i.d., days 1–14, every 3 weeks MBC patients unsuitable for intensive chemotherapy Stratified for institution, PS, liver or brain metastases, planned use of bisphosphonates/ prednisone Continuous capecitabine650mg/m2 b.i.d., days 1–21, every 3 weeks Classical CMFOral cyclophosphamide 100mg/m2 days 1–14i.v. methotrexate 40mg/m2 days 1, 8 i.v. 5-FU 600mg/m2 day 1, 8, every 4 weeks b.i.d. = twice daily; i.v. = intravenous; CMF = cyclophosphamide, methotrexate and 5-FU; PS = performance status Stockler MR, et al. J Clin Oncol 200725(Suppl. 18):39s (Abstract 1031)

  13. Capecitabine versus CMF baseline characteristics: a relatively young, fit population Int = intermittent; Cont = continuousECOG = Eastern Cooperative Oncology Group Stockler MR, et al. J Clin Oncol 200725(Suppl. 18):39s (Abstract 1031)

  14. Capecitabine versus CMF: similarresponse rates Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031)

  15. Capecitabine versus CMF: significantsurvival benefit with capecitabine 1.0 0.8 0.6 0.4 0.2 0 Median (months) Capecitabine (intermittent) + continuous 22 CMF 18 Log-rank p=0.02HR=0.72 (95% CI: 0.55–0.94) Proportion alive 0 6 12 18 24 30 36 42 48 Months Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031) HR = hazard ratio; CI = confidence interval

  16. Capecitabine monotherapy is well tolerated 50 40 30 20 10 0 † Grade 3/4 adverseevents (%) * * * * Other toxicities Alopecia Infection Hand-foot syndrome Stomatitis Febrile neutropenia Neutropenia *p≤0.0001 X versus CMF;†p=0.03 X versus CMF Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031)

  17. Capecitabine monotherapy has proven efficacy across all lines of therapy ORR = overall response rate 1Stockler MR, et al. J Clin Oncol 2007;25(Suppl. 18):39s (Abstract 1031) 2Bajetta E, et al. J Clin Oncol 2005;23:2155–61 3O’Shaughnessy J, et al. Ann Oncol 2001;12:1247–54; 4Talbot D, et al. Br J Cancer 2002;86:1367–72 5Soto C, et al. J Clin Oncol 2006;24(Suppl. 18):20s (Abstract 570) 6Blum J, et al. J Clin Oncol 1999;17:485–93 7Largillier R, et al. Ann Oncol 2006;17(S9) (Abstract 161P); 8Miller K, et al. J Clin Oncol 2005;23:792–9 9Mavroudis D, et al. J Clin Oncol 2006;24(Suppl. 18):42s (Abstract 658) 10Reichardt P, et al. Ann Oncol 2003;14:1227–33; 11Blum J, et al. Cancer2001;92:1759–68

  18. Capecitabine plus docetaxel first line significantly extends TTP: pivotal clinical trial 1.0 0.8 0.6 0.4 0.2 0 CD (n=255) Docetaxel (n=256) Log-rank p=0.0001; HR=0.652 Estimated probability 4.2 6.1 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812–23 CD = capecitabine + docetaxel

  19. Capecitabine plus docetaxel first line significantly extends OS: pivotal clinical trial 1.0 0.8 0.6 0.4 0.2 0 CD Docetaxel Log-rank p<0.01; HR=0.777 Estimated probability 11.5 14.5 0 4 8 12 16 20 24 28 32 36 40 44 48 Months Minimum follow-up = 27 months Miles D, et al. Clin Breast Cancer 2004;5:273–8

  20. CD: most common (>5%) grade 3/4 treatment-related toxicities 50 40 30 20 10 0 CD (n=251) Grade 3 Grade 4 Grade 3 Grade 4 Docetaxel (n=255) Patients (%) Hand-foot syndrome Fatigue/ asthenia Diarrhoea Stomatitis Nausea Neutropenic fever O’Shaughnessy J, et al. J Clin Oncol 2002;20:2812–23

  21. Phase III trial of capecitabine with docetaxelin anthracycline-resistant MBC (NO16853) Capecitabine b.i.d. 1,250mg/m2 days 1–14 every 3 weeks Docetaxel 75mg/m2 (60 minute) i.v. day 1 every 3 weeks RANDO MISATION Failure, or resistance to an anthracycline-based therapy given in the neoadjuvant, first or second-line metastatic setting and  two non-adjuvant regimens of chemotherapy Capecitabine b.i.d. 950mg/m2 day 1–14 every 3 weeks Docetaxel 75mg/m2 (60 minute) i.v. day 1 every 3 weeks Primary endpoint: equivalency in TTP or death Planned sample size: 440 patients

  22. Treatment scenario 2 • You are treating a patient with the following characteristics • HER2-negative, hormone receptor-negative MBC • no prior chemotherapy for metastatic disease • relatively young (45 years), with good PS • adjuvant therapy with anthracyclines, 3–4 years previously • What treatment would you recommend?

  23. Angiogenesis is essentialfor tumour growth Premalignant tumour Malignant tumour Tumourgrowth Vascularinvasion Micro- metastases Metastatic growth Angiogenicswitch Stages at which angiogenesis plays a role in tumour progression Adapted from Poon RT, et al. J Clin Oncol 2001;19:1207–25

  24. Bevacizumab binds VEGF,the key mediator of angiogenesis • Recombinant humanised monoclonal anti-VEGF antibody • humanised murine antibody(93% human, 7% murine) • prevents possible immune reactions • recognises and binds to all major isoforms of human VEGF-A • prevents VEGF from interacting with its receptors • results in the inhibition of activation of downstream signalling pathways • terminal half-life = 17–21 days • enables convenient combination with concomitant therapy schedules Bevacizumab VEGF X P– – P P– – P X Growth Proliferation Migration Survival VEGF = vascular endothelial growth factor

  25. Phase III trial of bevacizumab plus capecitabine in pretreated MBC (AVF2119g) Treat to disease progression† • Primary endpoint: PFS • secondary endpoints: ORR and OS • *Prior anthracycline and taxane treatment • one or two prior chemotherapy regimens for MBC, or • relapse within 12 months of completing anthracycline- and taxane-containing adjuvant therapy Capecitabine (n=230) Previously treated MBC* (n=462) †No cross over was permitted Capecitabine + bevacizumab 15mg/kg every 3 weeks (n=232) Treat to disease progression Capecitabine 1,250mg/m2 orally b.i.d. for2 weeks of a 3-week cycle Miller KD, et al. J Clin Oncol 2005;23:792–9

  26. AVF2119g: patient characteristics Miller KD, et al. J Clin Oncol 2005;23:792–9

  27. AVF2119g: efficacy summary • The addition of bevacizumab to capecitabine more than doubled the response rate according to an independent review facility NS = not significant Miller KD, et al. J Clin Oncol 2005;23:792–9

  28. AVF2119g: grade 3/4 adverse events *No grade 4 CHF = congestive heart failure Miller KD, et al. J Clin Oncol 2005;23:792–9

  29. Angiogenesis: redundancy in the system Breast cancer VEGF bFGF TGFb-1 PlGF PD-ECGF Pleiotrophin VEGF bFGF TGFb-1 PlGF PD-ECGF VEGF bFGF TGFb-1 PlGF VEGF bFGF TGFb-1 VEGF Tumour growth Bevacizumab may be more effective earlier in thecourse of MBC Adapted from Folkman J. In: DeVita VT, et al. editors. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2005. p. 2865–82

  30. Primary endpoint: PFS Other endpoints: ORR, OS, QoL E2100: phase III trial of first-line paclitaxel ± bevacizumab in MBC Paclitaxel (n=354) Treat to disease progression* Previously untreated locally recurrent or MBC (n=722) *No cross over permitted Paclitaxel + bevacizumab 10mg/kg every 2 weeks (n=368) Treat to disease progression Paclitaxel: 90mg/m2 every week for 3 weeks of a 4-week cycle Miller KD, et al. N Engl J Med 2007;357:2666–76 *No cross over permitted

  31. E2100: statistical design • Primary endpoint: PFS • 85% power for a 33% improvement • 6 vs 8 months • Final analysis after 546 PFS • interim analyses after 270 and 425 events • Safety analyses • grade 4 haemorrhage or hypertension (1% acceptable) • grade 3/4 thrombosis or embolism (5% acceptable) Miller KD, et al. N Engl J Med 2007;357:2666–76

  32. E2100: treatment arms were well balanced for major prognostic factors ER-positive = oestrogen receptor-positive; PR-positive = progesterone receptor-positive Data on file submitted to CHMP November 07

  33. Bevacizumab plus paclitaxel (E2100): PFS benefit confirmed by Independent Review Facility (IRF) 1.0 0.8 0.6 0.4 0.2 0 5.8 11.4 PFS estimate 5.8 11.3 0 6 12 18 24 30 36 Months *Scans available for 90% of patients Data on file submitted to CHMP November 07

  34. Paclitaxel Bevacizumab + paclitaxel Bevacizumab plus paclitaxel (E2100):consistent PFS benefit in subgroup analysis Increase inmedian PFS (%) Median PFS* 9 months Prior adjuvant hormonetherapy (n=343) 12.4 103 114 126 113 98 55 116 73 6.1 Prior adjuvantchemotherapy (n=475) 12.4 5.8 Prior adjuvant taxanetherapy (n=142) 13.1 5.8 Prior adjuvant anthracyclinetherapy (n=364) 12.8 6.0 Prior metastatic hormonetherapy (n=262) 11.9 6.0 11.9 ER-positive status (n=446) 7.7 24-month disease-freeinterval (n=296) 10.6 4.9 3 metastatic sites(n=208) 8.3 4.8 0 5 10 15 Months *PFS as assessed by IRF Data on file submitted to CHMP November 07

  35. E2100: objective response(patients with measurable disease) Investigator assessment(n=525) IRF assessment(n=472) 60 50 40 30 20 10 0 Bevacizumab + paclitaxel 50 48 Paclitaxel Best response (%) 23 22 CR + PRp<0.0001 CR + PRp<0.0001 Data on file submitted to CHMP November 07

  36. E2100: increased survival with bevacizumab was seen over the first 30 months 1.0 0.8 0.6 0.4 0.2 0 Median OS n (months) Bevacizumab + paclitaxel 368 26.5 Paclitaxel 354 24.8 81.4% Log-rank p=0.1374; HR=0.869 (95% CI: 0.722–1.046) 74.0% p=0.017* 55.0% OS estimate 50.1% p=0.191* 0 6 12 18 24 30 36 42 48 54 60 Months Data on file submitted to CHMP November 07 *Post-hoc

  37. E2100: increased survival with bevacizumab was seen over the first 30 months 1.0 0.8 0.6 0.4 0.2 0 Median OS n months Bevacizumab + paclitaxel 368 26.5 Paclitaxel 354 24.8 80% power to detect  OS 24–31 months 10–15% power to detect  OS of 3 months OS estimate 0 6 12 18 24 30 36 42 48 54 60 Months Data on file submitted to CHMP November 07

  38. E2100: most frequent grade 3adverse events (5% incidence) #Includes NCI AdEERS mandatory collection in the bevacizumab + paclitaxel arm only, which does not allow valid comparison between the two arms NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events Data on file submitted to CHMP November 07

  39. Less frequently reportedbevacizumab-related adverse events • CHF/cardiomyopathy • observed in 2.2% of patients treated with bevacizumab plus paclitaxel • caution should be exercised with patients experiencing clinically significant cardiac disease • ATE and VTE • observed in 3.6% and 3.0% of patients treated with bevacizumab plus paclitaxel • discontinue bevacizumab in patients with symptomatic pulmonary embolism and those who develop ATE • Wound-healing complications • severe wound-healing complications were observed in 1.1% of patients treated with bevacizumab plus paclitaxel • bevacizumab should not be initiated for ≥28 days following major surgery or in patients with unhealed wounds, and should be withheld for elective surgery • GI perforations • observed in <1% of patients treated with bevacizumab plus paclitaxel • permanently discontinue bevacizumab in patients experiencing GI perforation Data on file submitted to CHMP November 07; Avastin Summary of Product Characteristics (SmPC)

  40. E2100: quality of life TOI-B TOT-B • TOI-B (Trial Outcome Index) incorporates measures of physical, functional and breast cancer-specific quality of life • TOT-B (Total Score) includes emotional and social/family well-being in addition to the above Better Better 7 3 –1 –5 –9 –13 –17 –21 –25 –29 –33 –37 –41 7 3 –1 –5 –9 –13 –17 –21 –25 –29 –33 –37 –41 p=0.0006 (primary analysis) p<0.0001 p=0.0001 Mean change from baseline Mean change from baseline p=0.0001 Bevacizumab+ paclitaxelPaclitaxel Worse Worse Baseline Week 17 Week 33 Baseline Week 17 Week 33 Roche data on file submitted to regulatory authority in 2006

  41. E2100: summary • Substantial prolongation of PFS • living without the disease advancing and improvingdisease-related symptoms • delaying subsequent lines of therapy and associated side effects • Higher QoL • Superior 1-year survival • Positive risk:benefit ratio

  42. Bevacizumab plus docetaxel in first-line MBC (AVADO): phase III study design • Recruitment completed in March 2007 • target recruitment was exceeded and 736 patients have been enrolled • Primary endpoint: PFS • secondary endpoints: ORR, OS, safety, QoL • Data to be presented at ASCO 2008 Treat todiseaseprogression Docetaxel 100mg/m2 every 3 weeks + placebo Previously untreated HER2-negative locally recurrent or MBC (n=705) Treat todiseaseprogression Docetaxel + bevacizumab 7.5mg/kg every3 weeks PI: David Miles Treat todiseaseprogression Docetaxel + bevacizumab 15mg/kg every3 weeks

  43. Phase III trial of bevacizumab plus chemotherapy in first-line MBC (RIBBON 1) • Recruitment completed August 2007 • Primary endpoint: PFS • secondary endpoints: chemotherapy-specific PFS, objective response rate, OS, safety Randomisation Anthracycline-based or taxane or capecitabine + placebo Treat to disease progression* 1 Previously untreated MBC (n=1,239) 2 Anthracycline-based or taxane or capecitabine + bevacizumab 15mg/kg every 3 weeks Treat to disease progression* PI: Joyce O’Shaughnessy *Continuation or cross over to bevacizumab is allowed at the discretion of the investigator

  44. Safety study of bevacizumab plus chemotherapy in first-line MBC (MO19391) • Recruitment started Q3 2006 • planned in 510 centres from 38 countries worldwide • Primary endpoint: safety • secondary endpoints: time to disease progression, OS, safety in patients with CNS metastases Bevacizumab (10mg/kg every 2 weeks or 15mg/kg every 3 weeks)+taxane-based chemotherapy* Previously untreated HER2-negative locally recurrent or MBC(n~2,300) Treat to disease progression PI: Ian Smith *Taxane use according to routine practice or, if taxanes contraindicated, alternative chemotherapy allowed at physician’s discretion CNS = central nervous system Smith IE, et al. Eur J Cancer Suppl2007;5:221 (Abstract 2123)

  45. Rationale for combining bevacizumab with hormonal therapy • Evidence suggests that oestrogen directly modulates angiogenesis • regulatory regions of the VEGF gene contain elements responsive to oestrogen1 • oestrogen upregulates VEGF expression in a breast cancer cell line2 • aromatase inhibitors decrease VEGF levels in a rat model3 • The combination of bevacizumab and fulvestrant produced considerably greater growth suppression of breast cancer xenografts than either agent alone4 1Hyder SM, et al. Cancer Res 2000;60:3183–90; 2Takei H, et al. Breast Cancer 2002;9:39–42 3Nakamura J, et al. Endocrinology 1996;137:5589–964Pietras RJ, et al. Breast Cancer Res Treat 2006;100(Suppl. 1):S37 (Abstract 507)

  46. Trials of bevacizumab combined with hormonal therapies in MBC GEICAM 2006-11: phase III study of bevacizumab + letrozole Treat to disease progression Letrozole Postmenopausal women with advanced or MBC suitable for endocrine therapy Treat to disease progression Letrozole + bevacizumab15mg/kg q3w Primary endpoint: progression-free survival CALGB 40503: phase III trial of bevacizumab + endocrine agents Aromatase inhibitor or tamoxifen + bevacizumab 15mg/kg q3w Treat to disease progression ER+/PR+ previously untreated locally recurrent or MBC (n~360) Treat to disease progression Aromatase inhibitor or tamoxifen + placebo Primary endpoint: progression-free survival, response assessment every9 weeks

  47. Summary • Bevacizumab and capecitabine play integral roles in the treatment algorithm for HER2-negative MBC • Bevacizumab plus paclitaxel is effective and well tolerated and is suitable for most patients with MBC • Single-agent capecitabine has demonstrated efficacy across all lines of MBC therapy • Data from ongoing studies will further expand the use of these agents in MBC

More Related